Regulatory Surveillance Summary March 2019

Association for the Advancement of Medical Instrumentation (AAMI)

AAMI News: Draft Guidance ‘Leapfrogs’ FDA into Regulation of Brain – Computer Interfaces, April 2019

For people affected by paralysis or an amputation, devices that can bridge the gap between the brain and computers—called brain–computer interfaces (BCIs)—hold great promise. These devices can be implanted into the nervous system to allow limbs or other prosthetics to be controlled by the patient’s thoughts.  To help encourage the development of this emerging technology, the Food and Drug Administration (FDA) has released “leapfrog” draft guidance, Implanted Brain–Computer Interface (BCI) Devices for Patients with Paralysis or Amputation—Non-clinical Testing and Clinical Considerations, intended to provide the FDA’s “initial thoughts about regulatory considerations.”

“The idea that a prosthetic could interact with the brain has been the topic of much imagination, but now we’re actually on the verge of realizing this opportunity. The FDA has an important role to play by laying out a path for developers on how to seize this prospect and advance the development of new devices,” said outgoing FDA Commissioner Scott Gottlieb in a statement. “Our work on BCI devices also reflects our deep commitment to help the men and women who bravely served our country …we believe that BCI technology has the potential to improve wounded veterans’ lives and those of other Americans in regaining mobility and thus improving their quality of life.”  The draft guidance is intended to help device developers design clinical studies of BCI devices as well as conduct nonclinical device testing, utilizing relevant safety standards. The guidance document also describes methods to evaluate biocompatibility with human tissue (e.g., blood, cerebrospinal fluid), maintain compliance with electrical and electromagnetic safety standards, and establish compatibility with MRI machines and wireless signals. The FDA is seeking feedback on the draft guidance until April 26 at (docket FDA-2014-N-1130-0004). Read more.


United States Food and Drug Administration (US FDA) Guidances

Data Integrity and Compliance with Drug CGMP, Questions and Answers for Industry, December 2018

The Food and Drug Administration is announcing the availability of a final guidance for industry entitled Data Integrity and Compliance with Drug CGMP: Questions and Answers.  In recent years, FDA has increasingly observed current good manufacturing practice (CGMP) violations involving data integrity during CGMP inspections. This is troubling because ensuring data integrity is an important component of industry’s responsibility to ensure the safety, effectiveness, and quality of drugs, and of FDA’s ability to protect the public health. FDA expects that all data to be reliable and accurate. This guidance helps clarify the role of data integrity in CGMP for drugs.

CGMP regulations and guidance allow for flexible and risk-based strategies to prevent and detect data integrity issues. Companies should implement meaningful and effective strategies to manage their data integrity risks based on their process understanding and knowledge management of technologies and business models.  The guidance addresses specific questions about how data integrity relates to CGMP compliance, as well as more general data integrity concepts, in question and answer format.

Data Integrity and Compliance with Drug CGMP: Questions and Answers.


REMS Assessment: Planning and Reporting and Survey Methodologies to Assess REMS Goals that Relate to Knowledge, Drafts – January 2019

The US FDA issued two guidances that aim to bring clarity to the assessment of risk evaluation and mitigation strategies (REMS) programs. These guidances, “REMS Assessment: Planning and Reporting Guidance for Industry” and “Survey Methodologies to Assess REMS Goals That Relate to Knowledge Guidance for Industry,” will assist sponsors in assessing the effectiveness of REMS programs.

The REMS Assessment draft guidance aims to increase stakeholder understanding of how to develop a REMS Assessment Plan by specifically discussing how the REMS program goals, objectives, and REMS design may impact the selection of metrics and data sources, which will be used to assess whether the REMS is meeting its risk mitigation goals. It recommends assessing the REMS using both process measures and outcome measures and provides examples of metrics by assessment categories, and data sources that may be utilized to evaluate the performance of the REMS. It also includes considerations for assessing the impact of REMS on patient access to the drug or its burden to the healthcare delivery system. Finally, this guidance provides recommendations on a standard format that may be used to report assessment findings according to the timetable for submission of REMS assessments.

The REMS Survey Methodologies draft guidance provides recommendations to industry on conducting REMS assessment surveys used to evaluate respondent knowledge of REMS-related information. The majority of applicants use surveys to evaluate patients’ and healthcare providers’ understanding of the serious risks associated with, and safe use of, their drugs to assess REMS knowledge goals. This draft guidance discusses general principles and recommendations related to conducting REMS assessment knowledge surveys, including study design, survey data collection and processing, and data analysis. It also provides recommendations for developing patient and healthcare provider survey instruments (i.e., questionnaires).

REMS Assessment: Planning and Reporting Guidance for Industry and Survey Methodologies to Assess REMS Goals That Relate to Knowledge Guidance for Industry


Mitigation Strategies to Protect Food Against Intentional Adulteration, Drafts – March 2019

On March 5, 2019, the FDA released the second installment of a draft guidance document designed to support compliance with the Intentional Adulteration (IA) Rule under the FDA Food Safety Modernization Act (FSMA).  The FSMA final rule on intentional adulteration is designed to address hazards that may be intentionally introduced to foods, including by acts of terrorism, with the intent to cause wide-spread harm to public health. Unlike the other FSMA rules that address specific foods or hazards, the IA rule requires the food industry to implement risk-reducing strategies for processes in food facilities that are significantly vulnerable to intentional adulteration.  Food facilities covered by the rule will be required to develop and implement a food defense plan that identifies vulnerabilities and mitigation strategies for those vulnerabilities. These facilities will then be required to ensure that the mitigation strategies are working. The first compliance date for large facilities arrives in July 2019.

This installment adds to and incorporates elements of the previously published guidance with chapters covering topics such as:

  • The components of the food defense plan
  • How to conduct vulnerability assessments by using the four Key Activity Types method (bulk liquid receiving and loading, liquid storage and handling, secondary ingredient handling, mixing and similar activities)
  • Evaluating the Three Fundamental Elements (potential public health impact, degree of physical access to the product, ability of an attacker to successfully contaminate the product), or
  • Using the Hybrid Approach, which is a combination of the Key Activity Types and Three Fundamental Elements methods
  • How to identify and implement mitigation strategies
  • Food defense monitoring requirements
  • Education, training, and experience

This installment also includes the addition of food defense plan worksheets in Appendix 1 and a new appendix that includes detailed examples of vulnerability assessments using the Three Fundamental Elements and the Hybrid Approach.

This draft guidance, in its entirety, is intended to be a resource that will help the food industry implement the IA provisions in a flexible and cost-effective manner. During the 120-day comment period for this installment, stakeholders will also be able to provide comments on the first and second installments of the draft guidance.  A public meeting on the draft guidance is being planned and additional information will be made available in a forthcoming announcement.

FSMA Final Rule for Mitigation Strategies to Protect Food Against Intentional Adulteration and

Conversations with FVM: Protecting the Food Supply from Intentional Adulteration, such as Acts of Terrorism **Updated**


United States Food and Drug Administration (US FDA) Recalls

GE Healthcare Recalls CareScape R860 Inspiratory Safety Guard Due to Risk of Disconnection from Breathing Circuit, October 2018

GE Healthcare’s CareScape R860 Inspiratory Safety Guard is a breathing accessory designed for use with the Carescape R860 Ventilator. The Carescape R860 Ventilator provides mechanical ventilation and breathing support to infants, children, and adult patients. The Carescape R860 Ventilator and the CareScape R860 Inspiratory Safety Guard are designed for use only under a healthcare professional’s order within or during transport between medical facilities.  GE Healthcare is recalling the CareScape R860 Inspiratory Safety Guard due to the risk of the device disconnecting from the patient’s breathing circuit. As the result of a manufacturing defect, the safety guard’s outlet connector may have incorrect dimensions, which could result in the device not having a secure fit with the breathing circuit. This may result in the patient not receiving breathing support.  No patient injuries have been reported, although there remains a risk of ventilation and oxygen-loss (hypoxia) should the patient’s airway become disconnected from the breathing circuit.


Dr. Reddy’s Laboratories Continues its Voluntary Nationwide Recall of Levetiracetamin 0.54% Sodium Chloride Injection 1500 mg/100 mL Due to Mislabeling, February 2019

Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY) announced that it’s wholly owned subsidiary, Dr Reddy’s Laboratories, Inc is continuing its voluntary nationwide recall of lot ABD807 of Levetiracetram in 0.54% Sodium Chloride Injection, 1,500 mg/100 mL (15 mg/mL) single-dose infusion bags to the hospital level in U.S.A.  The recall, which began in October 2018, was originally initiated due to a product complaint received for mislabeling. The pre-printed text content on the infusion bag (primary container) for the lot indicates product information as Levetiracetam in 0.75% Sodium Chloride Injection (1000mg/100ml). The label on the external foil pouch has the product information as Levetiracetam in 0.54% Sodium Chloride Injection (1500mg/100ml). To date, there have been no reports of adverse events related to this recall. Read more.


Mylan Institutional LLC Initiates Voluntary Nationwide Recall of Levleucovorin Injection Due to the Presence of Particulate Matter, March 2019

Mylan Institutional LLC is conducting a voluntary nationwide recall of two lots of Levoleucovorin Injection, 250 mg/25 mL to the consumer/user level. The lots were manufactured by Alidac Pharmaceuticals Limited and distributed by Mylan Institutional LLC. The Levoleucovorin Injection is being recalled due to the presence of particulate matter identified as copper salts. The particulate matter was discovered during 12-month stability testing.  Administration of a sterile injectable that has foreign particulates has the potential of severe health consequences. Intravenous administration of a solution containing particulates could lead to local irritation, vasculitis/phlebitis, antigenic or allergic reactions, and microvascular obstruction, including pulmonary embolism. To date, Mylan has not received any reports of adverse events related to this recall.  Levoleucovorin injection is indicated for rescue after high-dose Methotrexate therapy in osteosarcoma; for diminishing the toxicity and counteracting the effects of impaired Methotrexate elimination and of inadvertent overdose of folic acid antagonists; and for the use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. Read more.


United States Food and Drug Administration (US FDA) Consent Decrees and Warning Letters

Federal Court Enters Consent decree Against Ranier’s Rx Laboratory and Owner for Manufacturing Purportedly Sterile Drug Products in Insanitary Conditions, February 2019

The U.S. District Court for the Western District of Pennsylvania entered a consent decree of permanent injunction today between the United States and Ranier’s Rx Laboratory Inc., doing business as Ranier’s Compounding Laboratory, of Jeanette, Pennsylvania, and pharmacist Francis H. Ranier, who owns the compounding facility.  “We continue to see concerning activity when it comes to some compounded drugs, including problems related to the conditions under which compounded sterile medicines are made, which can raise significant risks to patients. This is an area of intense focus for the FDA. We’re committed to making sure that compounded drugs are made under appropriate production standards and, when necessary, taking enforcement actions against compounders who fail to produce sterile drugs in compliance with the law,” said FDA Commissioner Scott Gottlieb, M.D. “Despite our warning, Ranier’s and its owner placed patients at risk by compounding purportedly sterile drug products under insanitary conditions. The FDA will continue to pursue enforcement action against companies and owners who place American consumers at risk.”  The consent decree prohibits Ranier’s and its owner from, among other things, manufacturing, holding, or distributing human or animal sterile drugs compounded at their facility until they comply with the Federal Food, Drug, and Cosmetic (FD&C) Act and FDA regulations.

Ranier’s Rx Laboratory


FDA Issues Warning Letters to Two Breast Implant Manufacturers for Failure to Comply with Post-Approval Study Requirements, March 2019

FDA issued warning letters to two breast implant manufacturers for failure to comply with their requirements, under their pre-market approval orders, to conduct post-approval studies to assess the long-term safety and risks of their silicone gel-filled breast implants.  The FDA issued warning letters to Mentor Worldwide LLC of Irvine, California, and Sientra, Inc. of Santa Barbara, California. Every manufacturer of approved silicone gel-filled breast implants is required to conduct post-approval studies to further evaluate safety and effectiveness of the products and to answer additional scientific questions about the long-term safety and potential risks of breast implants that their pre-market clinical trials were not designed to answer.

“Post-approval requirements are critical to ensuring the safety and effectiveness of the medical products we regulate and we’ll continue to hold manufacturers accountable when they fail to fulfill these obligations,” said FDA Commissioner Scott Gottlieb, M.D. “We’re issuing these warning letters based on the manufacturers’ low recruitment, poor data, and low follow-up rates in their required post-approval studies. We expect these manufacturers to meet the pre-specified study requirements in order to ensure the collection of long-term data that can be used to inform long-term patient safety.  Post-approval studies, along with other surveillance tools such as adverse event reports, registries, and scientific literature, allow the FDA to help ensure the safety of medical devices and protect patients.”

Read the FDA news release “FDA issues warning letters to two breast implant manufacturers for failure to comply with post-approval study requirements”